Mechanism: FOXP1 interacts with CBP/β-catenin/TCF7L2 at promoters and enhances β-catenin acetylation by CBP.

Impact: WNT-directed therapy may limit progression of DLBCL tumors with high FOXP1 expression.

Mutations in components of the WNT/β-catenin pathway result in constitutive signaling in several types of human cancers. However, aberrant activation of this pathway has also been observed in the absence of such mutations in many tumors, suggesting that other factors regulate WNT/β-catenin signaling. Walker and colleagues used a gain-of-function screen to identify the transcription factor forkhead box P1 (FOXP1), which has been implicated as an oncogene in B-cell lymphomas, as a candidate regulator of the WNT/β-catenin pathway. FOXP1 expression potentiated WNT/β-catenin transcriptional activity in a range of cell types, including diffuse large B-cell lymphoma (DLBCL) cells, and in the developing zebrafish embryo. FOXP1 was not sufficient to activate WNT signaling on its own, but instead acted downstream of the β-catenin destruction complex to enhance β-catenin–dependent transcription in response to stimulation with WNT ligand. FOXP1 promoted CREB-binding protein (CBP)–mediated acetylation of β-catenin at Lys49, which was necessary for FOXP1-driven potentiation of β-catenin activity. Furthermore, FOXP1 formed a complex with CBP, β-catenin, and transcription factor 7–like 2 (TCF7L2), which facilitates β-catenin function, at the promoters of WNT target genes. The ability of FOXP1 to enhance β-catenin–dependent transcription required the interaction of FOXP1 and TCF7L2 on DNA, and the DNA binding sites for these two proteins were significantly colocalized in multiple cell lines. Examination of human DLBCL cell lines revealed that WNT/β-catenin signaling was active in cells expressing FOXP1 and that FOXP1 expression correlated with sensitivity to WNT inhibitors. Furthermore, silencing FOXP1 or blocking WNT signaling inhibited tumor growth in a mouse xenograft model. These results highlight an important role for FOXP1 in the activation of WNT/β-catenin signaling and suggest that targeting the WNT pathway in tumors expressing high levels of FOXP1 may be beneficial in DLBCL.